Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome

Orrin Devinsky, Anup D Patel, Elizabeth A Thiele, Matthew H Wong, Richard Appleton, Cynthia L Harden, Sam Greenwood, Gilmour Morrison, Kenneth Sommerville, GWPCARE1 Part A Study Group, Angus Wilfong, Robert Flamini, Linda Laux, Ian Miller, Helen Cross, Charuta Joshi, Richard Chin, Sameer Zuberi, Orrin Devinsky, Anup D Patel, Elizabeth A Thiele, Matthew H Wong, Richard Appleton, Cynthia L Harden, Sam Greenwood, Gilmour Morrison, Kenneth Sommerville, GWPCARE1 Part A Study Group, Angus Wilfong, Robert Flamini, Linda Laux, Ian Miller, Helen Cross, Charuta Joshi, Richard Chin, Sameer Zuberi

Abstract

Objective: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.

Methods: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.

Results: Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC0-t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.

Conclusions: Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated.

Classification of evidence: This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

Copyright © 2018 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Disposition of patients
Figure 1. Disposition of patients
There was a delay of ≥23 weeks between treatment completion and when the open-label extension trial was available for enrollment. All pharmacokinetic analyses were conducted using the safety analysis set. CBD = cannabidiol.
Figure 2. Plasma pharmacokinetics (PK) of cannabidiol…
Figure 2. Plasma pharmacokinetics (PK) of cannabidiol (CBD) and metabolites
(A) Arithmetic mean plasma concentrations of CBD, 6-hydroxy-cannabidiol (6-OH-CBD), and 7-carboxy-cannabidiol (7-COOH-CBD) over time at baseline (day 1) and end of treatment (day 22). Note that the day 1 dose was 1.25 mg/kg for all 3 treatment groups. (B) Dose linearity for CBD, 6-OH-CBD, and 7-COOH-CBD exposures (based on area under the curve [AUC]0–t) at end of treatment (day 22). Qualitative data generated for the 7-OH-CBD metabolite also showed a dose-proportional increase. R2 values relate to geometric mean fitted regression lines.
Figure 3. Percentage change from baseline to…
Figure 3. Percentage change from baseline to end of treatment in plasma clobazam (CLB) and N-desmethylclobazam (N-CLB) concentrations
(A) By treatment group. Note that 2 patients in the 5 mg/kg/d cannabidiol (CBD) group reduced CLB dose during treatment, but no reason was listed. (B) By stiripentol use in all patients on CBD. Error bars: SEM.

References

    1. Devinsky O, Cross JH, Laux L, et al. . Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011–2020.
    1. O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: a review. Epilepsy Behav 2017;70:341–348.
    1. Devinsky O, Marsh E, Friedman D, et al. . Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol 2016;15:270–278.
    1. Gofshteyn JS, Wilfong A, Devinsky O, et al. . Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome (FIRES) in the acute and chronic phases. J Child Neurol 2017;32:35–40.
    1. Hess EJ, Moody KA, Geffrey AL, et al. . Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex. Epilepsia 2016;57:1617–1624.
    1. Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev 2014;46:86–95.
    1. Patsalos PN, Perucca E. Clinically important drug interactions in epilepsy: general features and interactions between antiepileptic drugs. Lancet Neurol 2003;2:347–356.
    1. Friedman D, Devinsky O. Cannabinoids in the treatment of epilepsy. N Engl J Med 2015;373:1048–1058.
    1. Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia 2017;58:1586–1592.
    1. Geffrey AL, Pollack SF, Bruno PL, Thiele EA. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia 2015;56:1246–1251.
    1. Posner K, Brent D, Lucas C, et al. . Columbia-Suicide Severity Rating Scale (C-SSRS): Children's Baseline/Since Last Visit (version 6/23/2010). New York:Research Foundation for Mental Hygiene; 2008.
    1. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers 2007;4:1770–1804.
    1. Hashi S, Yano I, Shibata M, et al. . Effect of CYP2C19 polymorphisms on the clinical outcome of low-dose clobazam therapy in Japanese patients with epilepsy. Eur J Clin Pharmacol 2015;71:51–58.
    1. Friedman D, Cilio MR, Tilton N, et al. . The effect of epidiolex (cannabidiol) on serum levels of concomitant anti-epileptic drugs in children and young adults with treatment-resistant epilepsy in an expanded access program. American Epilepsy Society 2014 annual meeting. Abstract No 2.309. Available at: . Accessed September 29, 2017.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner